This project encompasses two major objectives. One is to uncover and describe naturally occurring delayed-type iso-hypersensitivities (DIH) towards heritable iso-antigens, to determine the function of DIH, to use it to establish immunological principles, and to seek adverse or beneficial health-oriented conditions controlled by DIH. Instances of iso-reactivity have been described. In guinea pigs DIH can best be detected by delayed dermal reactions to an iso-antigenic heritable serum factor. The second, described with M. Howe and A. Goldstein in mice, is revealed by neonatal T cells replicating in the presence of mitomycin-treated isogeneic, adult splenic B cells possessing a different cell marker than that in the second instance. The other objective is to delineate principles of immuno-regulation. For this purpose we use three separate systems. One experimental model involves the use of dextran as an immunological probe. Its administration to guinea pigs and ice markedly changes humoral antibody and delayed type hypersensitivity responses to unrelated antigens and hapten. These alterations are caused by T cell products, the release of which is triggered by dextran. Another avenue of experimentation deals with the M to G shift in antibody synthesis. We have described a B cell product from secondary immune responses that recruits greater numbers of IgG synthesizing cells during a primary immune response. This humoral component is distinct from antibody and from T cell replacing factor. A third system utilizes congenital asplenia to determine the extent of splenic influence on immunocompetence. Hereditarily spleenless mice synthesize depressed amounts of IgM and IgG antibodies but demonstrate intact cellular immunity and tolerance induction. Further, bone marrow and thymic cells from asplenic mice were found to be incapable to make normal antibody responses to sheep erythrocytes. Presently we are looking at splenic influence upon development of lymphoid cell differentiation antigens and acquisition of functions.